1. Field of the Invention
The present invention relates to compounds that are selective chemotherapeutic agents which selectively target folate receptors (FR) of cancerous tumor cells and inhibit purine synthesis and hence, DNA synthesis. Specifically, the present invention relates to fused cyclic pyrimidines, having unique bridge region variations of pyrrolo[2,3-d]pyrimidines that include three and four atom amide and urea and carbamate linkages, which selectively target folate receptors (“FR”), particularly, FR-alpha and FR-beta of cancerous tumor cells. Methods of preparing and using these compounds are also provided.
2. Description of the Prior Art
Cancer chemotherapy agents as taught, for example in U.S. Pat. No. 5,939,420 to Gangjee, do not specifically selectively target cancer tumor cells. However, chemotherapy agents have targeted both normal and tumor cells. This lack of selectivity for tumor cells results in cytotoxicity to the normal cells and is also one of the major causes of chemotherapeutic failure in the treatment of cancer. Further, advanced stage and platinum resistant tumors may be difficult to treat with traditional chemotherapeutic agents such as, but not limited to, carboplatin or paclitaxel (docitaxel). Other documents in this area include J. Med. Chem. 48 (16), 5329-5336, web release date Jul. 9, 2005 “Synthesis of Classical Four-Carbon Bridged 5-Substituted Furo-[2-3-d]-Pyrimidine and 6-Substituted Pyrrolo-[2,3-d]-Pyrimidine Analogues as Antifolates” by A. Gangjee et al.
As is known in the prior art, a type of folate receptors FR, particularly, FR-alpha and FR-beta, is overexpressed on a substantial amount of certain surfaces of a number of cancerous tumors including, but not limited to, ovarian, endometrial, kidney, lung, mesothelioma, breast, and brain tumors.
In most normal tissues, the FR-alpha and FR-beta are not present. In most normal tissues, folic acid is not taken up by normal cells by way of a reduced folate carrier system (RFC). In light of the specificity of the folic acid, conjugates of folic acid have been used in the prior art to selectively deliver toxins, liposomes, imaging and cytotoxic agents to FR-alpha expressing tumors.
However, one of the major limitations of the foregoing, such as cytotoxic-folic acid conjugates, is that this requires cleavage from the folic acid moiety to release the cytotoxic drug. Even more importantly, premature release of the cytotoxic agent during the transport before reaching the tumor destroys selectivity and thereby leads to undesired toxicity in normal cells. This is a very serious detriment scientifically and commercially.
Further, if the folic acid moiety of the cytotoxic-folic acid conjugate is difficult to cleave, then the anti-tumor activity is hindered as a result of the inability or reduced ability to release the cytotoxic agent. Accordingly, treatment of the tumor cells with the cytotoxic agent is either hindered or rendered nil as a result of the difficulty in cleaving the cytotoxic agent moiety from the folic acid-based conjugate.
In spite of the foregoing prior art, however, there remains a very real need for compositions that selectivity target the FR of tumor cells.
An object of this invention is to provide compositions for selectively targeting FR, in particular, FR-alpha and FR-beta, of tumor cells with a cancer-treating agent that inhibits purine synthesis and hence, DNA synthesis.
In a related object, the compound does not contain conjugated compositions and does not need cleavage to release a cytotoxic drug.
In yet another related object, the compound will allow penetration into the cancerous cells expressing FR, that is, FR-alpha and/or FR-beta, but not into a cell using the reduced folate carrier system (RFC).
Another object of this invention is to provide a non-toxic FR targeting compound to the cancerous tumor in the process of treating a patient.
Another object of this invention is to efficiently target a cancerous tumor.
Another object of this invention is to utilize an essentially noncompound useful in treating a cancerous tumor.